The role of interleukin-25-producing T-helper-cells during colitis-associated and spontaneous colon tumorigenesis

结直肠癌是一种常见的恶性疾病，包括各种亚型，其治疗选择仍然不足。白细胞介素-25是白细胞介素-17家族的一种细胞因子，在肠道免疫稳态和抗感染防御中发挥核心作用。除了肠上皮细胞，已知的白细胞介素-25的来源，我们现在可以证明存在的白细胞介素-25产生的T辅助细胞在肠道。包括我们自己的初步工作在内的几个指标表明，这种新的T细胞分化系在结直肠癌的发展中具有病理学意义。该项目的目的是详细强调产生白细胞介素-25的T辅助细胞对肠道肿瘤发生的重要性。在这个建议的中心是在体内实验与完善的实验模型和肠道肿瘤发生的分子分析。本研究基于以下假设：1）Th 25细胞启动IL-13+ NKT细胞介导的小鼠溃疡性结肠炎，并支持结肠炎相关的肿瘤进展。IL-13+ NKT细胞的分化主要由Th 25细胞（而不是由产生IL-25的上皮细胞）诱导。2)肿瘤浸润性Th 25细胞通过颗粒酶B和穿孔素介导免疫肿瘤控制，并抑制自发性结肠肿瘤的进展。该项目将回答以下问题：1）缺乏产生白细胞介素-25的淋巴细胞是否会影响肠道屏障功能或结肠中的细菌移位？2)在结肠炎相关性和自发性结肠肿瘤发生过程中，是否存在不同的Th 25细胞（特别是肿瘤浸润性Th 25细胞）分布模式，是否可以检测到颗粒酶B和穿孔素表达的改变？3)在AOM-恶唑酮肿瘤模型中，慢性恶唑酮结肠炎是否需要Th 25细胞？Th 25细胞是否促肿瘤发生或超过其对肿瘤细胞的细胞毒活性？4)分泌的IL-25是否主要通过修饰炎症反应介导其对免疫细胞的作用，或直接介导其对IL-17 RB+肠上皮/肿瘤细胞的作用？5）Th 25细胞浸润与溃疡性结肠炎局部炎症活动及散发性结直肠癌患者肿瘤分期是否相关？从人溃疡性结肠炎或散发性结直肠癌中分离的Th 25细胞之间是否存在任何分子差异？因此，该项目的目标是研究产生白细胞介素-25的T辅助细胞在结直肠癌形成和生长中的作用，并探索干预这种免疫级联反应的潜在机会。

Colorectal cancer is a common and malignant disease that includes various subtypes and their therapeutic options are still insufficient. Interleukin-25 is a cytokine of the interleukin-17 family and plays a central role in the intestinal immune homeostasis and defense against infection. In addition to intestinal epithelial cells, the known source of interleukin-25, we can now demonstrate the existence of interleukin-25-producing T helper cells in the intestine. Several indicators, including our own preliminary work suggest a pathological significance of this new line of T-cell differentiation in the development of colorectal carcinomas. The aim of the project is to highlight the importance of interleukin-25-producing T helper cells for intestinal tumorigenesis in detail. In the center of this proposal are in vivo experiments with well-established experimental models and the molecular analysis of intestinal tumorigenesis. This project is subject to the following hypotheses : 1) Th25 cells initiate IL-13+ NKT-cell-mediated murine ulcerative colitis and support colitis-associated tumor progression. The differentiation of IL-13+ NKT-cells is mainly induced by Th25 cells (not by IL-25-producing epithelial cells). 2) Tumor-infiltrating Th25 cells mediate an immunological tumor control via granzyme B and perforin and suppress the progression of spontaneous colon tumors. The project will answer the following questions: 1) Does the absence of interleukin-25-producing lymphocytes affect intestinal barrier function or bacterial translocation in the colon? 2) Is there a different distribution pattern of Th25 cells (in particular tumor-infiltrating Th25 cells) and can an alteration of granzyme B and perforin expression be detected during colitis-associated and spontaneous colon tumorigenesis? 3) Are Th25 cells necessary for the chronic oxazolone colitis in the AOM-oxazolone tumor model and are Th25 cells pro-tumorigenic or outweighs their cytotoxic activity against tumor cells? 4) Does secreted IL-25 mediate its effects mainly on immune cells via modification of the inflammatory response or directly on IL-17RB+ intestinal epithelial/tumor cells? 5 ) Is there a correlation of the infiltration by Th25 cells with the local inflammatory activity in human ulcerative colitis and with tumor stage of patients with sporadic colorectal cancer? Are there any molecular differences between Th25 cells isolated from human ulcerative colitis or sporadic colorectal cancer? The target of this project thus is to examine the role of interleukin-25-producing T helper cells in the formation and growth of colorectal cancer and explore potential opportunities for intervention in this immunological cascade.